In early 1980s Cech and Altman discovered that RNA molecule can catalyze chemical reaction in the absence of proteins or external energy. This breakthrough changed the central dogma in biosciences and gave rise to “The RNA World” hypothesis of the origin of life. Over the last two decades, numerous natural RNA motifs with catalytic activity have been discovered and many more engineered through methods of in vitro evolution. Utilizing the catalytic core of some ribozymes, trans-acting molecules that catalyze the site-specific cleavage of other RNA molecules, were engineered. This led to exploring the application of ribozymes as a new class of therapeutic agents that interfere with or repair dysfunctional RNAs in wide range of pathologies. Significant progress has been made towards this goal and the first generation therapeutic ribozymes are now being evaluated in clinical trials. The possibility for the treatment of genetic disorders, cancer, infectious diseases, autoimmune diseases and others raise significant interest in this emerging field of medical research.